Dysfunction of the androgen receptor (AR) signalling axis plays a pivotal role in the development and progression of prostate cancer (PCa). Steroidal and non-steroidal AR antagonists can significantly improve the survival of PCa patients by blocking the action of the endogenous ligand through binding to the hormone receptor and preventing its activation. Herein, we report two synthetic strategies, each utilizing the advantages of microwave irradiation, to modify the A-ring of natural androgen 5α-dihydrotestosterone (DHT) with pyridine scaffolds. Treatment of DHT with appropriate Mannich salts led to 1,5-diketones, which were then converted with hydroxylamine to A-ring-fused 6'-substituted pyridines. To extend the compound library with 4',6'-disubstituted analogues, 2-arylidene derivatives of DHT were subjected to ring closure reactions according to the Kröhnke's pyridine synthesis. The crystal structure of a monosubstituted pyridine product was determined by single crystal X-ray diffraction. AR transcriptional activity in a reporter cell line was investigated for all novel A-ring-fused pyridines and a number of previously synthesized DHT-based quinolines were included to the biological study to obtain information about the structure-activity relationship. It was shown that several A-ring-fused quinolines acted as AR antagonists, in comparison with the dual or agonist character of the majority of A-ring-fused pyridines. Derivative 1d (A-ring-fused 6'-methoxyquinoline) was studied in detail and showed to be a low-micromolar AR antagonist (IC50 = 10.5 μM), and it suppressed the viability and proliferation of AR-positive PCa cell lines. Moreover, the candidate compound blocked the AR downstream signalling, induced moderate cell-cycle arrest and showed to bind recombinant AR and to target AR in cells. The binding mode and crucial interactions were described using molecular modelling.
- MeSH
- androgenní receptory metabolismus MeSH
- antagonisté androgenních receptorů farmakologie MeSH
- dihydrotestosteron * farmakologie metabolismus MeSH
- lidé MeSH
- mikrovlny MeSH
- nádorové buněčné linie MeSH
- nádory prostaty * farmakoterapie metabolismus MeSH
- pyridiny farmakologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
High expression of the androgen receptor (AR) and the disruption of its regulation are strongly responsible for the development of prostate cancer (PCa). Therapeutically relevant non-steroidal or steroidal antiandrogens are able to block the AR effect by eliminating AR-mediated signalling. Herein we report the synthesis of novel steroidal pyrazoles derived from the natural sex hormone 5α-dihydrotestosterone (DHT). 2-Ethylidene or 2-(hetero)arylidene derivatives of DHT obtained by regioselective Claisen-Schmidt condensation with acetaldehyde or (hetero)aromatic aldehydes in alkaline ethanol were reacted with monosubstituted hydrazines to give A-ring-fused 1,5-disubstituted pyrazoles as main or exclusive products, depending on the reaction conditions applied. Spontaneous or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)-induced oxidation of the primarily formed pyrazolines resulted in the desired products in moderate to good yields, while 17-oxidation also occurred by using the Jones reagent as a strong oxidant. Transcriptional activity of the AR in a reporter cell line was examined for all novel compounds, and several previously synthesized similar DHT-based pyrazoles with differently substituted heteroring were also included to obtain information about the structure-activity relationship. Two specific regioisomeric groups of derivatives significantly diminished the transcriptional activity of the AR in reporter cell line in 10 μM concentration, and displayed reasonable antiproliferative activity in AR-positive PCa cell lines. Lead compound (3d) was found to be a potent AR antagonist (IC50 = 1.18 μM), it generally suppressed AR signalling in time and dose dependent manner, moreover, it also led to a sharp decrease in wt-AR protein level probably caused by proteasomal degradation. We confirmed the antiproliferative activity of 3d in AR-positive PCa cell lines (with GI50 in low micromolar ranges), and its cellular, biochemical and in silico binding in AR ligand-binding domain. Moreover, compound 3d was shown to be potent even ex vivo in patient-derived tissues, which highlights the therapeutic potential of A-ring-fused pyrazoles.
- MeSH
- androgenní receptory metabolismus MeSH
- dihydrotestosteron * farmakologie metabolismus MeSH
- down regulace MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory prostaty * farmakoterapie metabolismus MeSH
- pyrazoly MeSH
- steroidy terapeutické užití MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Sexual size dimorphism (SSD) reflects sex-specific solutions to the allocation of energy among growth, reproduction and survival; however, the proximate mechanisms behind these solutions are still poorly known even in vertebrates. In squamates, sexual differences in body size used to be attributed to direct energy allocation to energetically demanding processes, largely to reproduction. In addition, SSD is assumed to be controlled by specific endogenous mechanisms regulating growth in a sex-specific manner, namely masculinization by male gonadal androgens or feminization by ovarian hormones. We performed a manipulative growth experiment in females of the male-larger gecko Paroedura picta in order to test the reproductive cost hypothesis, the male androgen hypothesis and the ovarian hormone hypothesis. Specifically, we investigated the effect of total ovariectomy, prepubertal ovariectomy, unilateral ovariectomy, and total ovariectomy followed by exogenous estradiol, dihydrotestosterone or testosterone treatment, on female growth in comparison to males and reproductively active females. The present results and the results of our previous experiments do not support the hypotheses that SSD reflects direct energy allocation to reproduction and that male gonadal androgens are involved. However, all lines of evidence, particularly the comparable growth of reproducing intact and unilaterally ovariectomized females, were concordant with the control of SSD by ovarian hormones. We suggest that feminization of growth by female gonadal hormones should be taken into consideration as an endogenous pathway responsible for the ontogeny of SSD in squamates.
- MeSH
- dihydrotestosteron metabolismus MeSH
- estradiol metabolismus MeSH
- ještěři růst a vývoj fyziologie MeSH
- ovarektomie MeSH
- ovarium růst a vývoj fyziologie MeSH
- pohlavní dimorfismus MeSH
- rozmnožování MeSH
- testosteron metabolismus MeSH
- velikost těla MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Human DHRS7 (SDR34C1) is one of insufficiently described enzymes of the short-chain dehydrogenase/reductase superfamily. The members of this superfamily often play an important pato/physiological role in the human body, participating in the metabolism of diverse substrates (e.g. retinoids, steroids, xenobiotics). A systematic approach to the identification of novel, physiological substrates of DHRS7 based on a combination of homology modeling, structure-based virtual screening and experimental evaluation has been used. Three novel substrates of DHRS7 (dihydrotestosterone, benzil and 4,4'-dimetylbenzil) have been described.
Dehydroepiandrosterone (DHEA) and its sulfate bound form (DHEAS) are important steroids of mainly adrenal origin. They are produced also in gonads and in the brain. Dehydroepiandrosterone easily crosses the brain-blood barrier and in part is also produced locally in the brain tissue. In the brain, DHEA exerts its effects after conversion to either testosterone and dihydrotestosterone or estradiol via androgen and estrogen receptors present in the most parts of the human brain, through mainly non-genomic mechanisms, or eventually indirectly via the effects of its metabolites formed locally in the brain. As a neuroactive hormone, DHEA in co-operation with other hormones and transmitters significantly affects some aspects of human mood, and modifies some features of human emotions and behavior. It has been reported that its administration can increase feelings of well-being and is useful in ameliorating atypical depressive disorders. It has neuroprotective and antiglucocorticoid activity and modifies immune reactions, and some authors have also reported its role in degenerative brain diseases. Here we present a short overview of the possible actions of dehydroepiandrosterone and its sulfate in the brain, calling attention to various mechanisms of their action as neurosteroids and to prospects for the knowledge of their role in brain disorders.
- MeSH
- androgeny metabolismus MeSH
- centrální nervový systém embryologie MeSH
- dehydroepiandrosteron analogy a deriváty metabolismus MeSH
- dehydroepiandrosteronsulfát metabolismus MeSH
- dihydrotestosteron metabolismus MeSH
- gonády metabolismus MeSH
- kyslík metabolismus MeSH
- lidé MeSH
- mozek metabolismus MeSH
- nadledviny metabolismus MeSH
- steroidy metabolismus MeSH
- testosteron metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- MeSH
- acne vulgaris * etiologie farmakoterapie patofyziologie MeSH
- androgenní receptory genetika metabolismus MeSH
- androgeny * metabolismus MeSH
- antagonisté androgenů * terapeutické užití MeSH
- dihydrotestosteron metabolismus MeSH
- hyperandrogenismus patofyziologie MeSH
- inhibitory 5-alfa-reduktasy terapeutické užití MeSH
- kontraceptiva orální hormonální terapeutické užití MeSH
- kontraceptiva orální kombinovaná terapeutické užití MeSH
- lidé MeSH
- testosteron metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Alpha-hexachlorocyclohexane (alpha-HCH), a part of the HCH pesticide mixture, is one of the most widespread persistent organic pollutants. Interestingly, only limited number of studies addressed the toxicity of alpha-HCH and the effects of its individual optical isomers have not been investigated in detail. In the present study we separated two alpha-HCH enantiomers by preparative HPLC and studied their activities towards androgen receptor (AR) using the MDA-kb2 cell line stably transfected with the luciferase reporter gene under the control of AR. There was no direct effect of alpha-HCH on AR but both isomers significantly suppressed the activity of AR in co-exposure with the natural ligand dihydrotestosterone in a concentration-dependent manner. One of the enantiomers appeared to be more active at lower concentration, which was also supported by the molecular modeling calculations with AR that showed a slight difference in estimated free energy of binding and inhibition constant between two enantiomers. Although studies with other pesticides demonstrated strong enantioselective differences in toxicity, the present research shows rather minor differences in modulations of AR by both alpha-HCH enantiomers. For the first time, enantioselective effects of alpha-HCH were demonstrated and the results suggest interaction with multiple regulatory events controlling the AR activity. Full elucidation of the toxicity mechanism will require further research.
- MeSH
- androgenní receptory metabolismus MeSH
- buněčné linie MeSH
- dihydrotestosteron metabolismus farmakologie MeSH
- hexachlorcyklohexan chemie metabolismus farmakologie MeSH
- isomerie MeSH
- lidé MeSH
- luciferasy MeSH
- reportérové geny MeSH
- transfekce MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- dihydrotestosteron metabolismus terapeutické užití MeSH
- lidé MeSH
- nemoci endokrinního systému diagnóza terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- biografie MeSH
- novinové články MeSH
- rozhovory MeSH
- MeSH
- androgeny metabolismus MeSH
- dehydroepiandrosteronsulfát metabolismus MeSH
- dihydrotestosteron metabolismus MeSH
- folikuly stimulující hormon metabolismus MeSH
- globulin vázající pohlavní hormony metabolismus MeSH
- kognice fyziologie MeSH
- kognitivní poruchy metabolismus MeSH
- lidé MeSH
- luteinizační hormon metabolismus MeSH
- pohlavní steroidní hormony fyziologie metabolismus MeSH
- prolaktin metabolismus MeSH
- testosteron metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- souhrny MeSH
- MeSH
- alopecie metabolismus MeSH
- androgenní receptory metabolismus MeSH
- androgeny fyziologie metabolismus MeSH
- cholestenon-5-alfa-reduktasa metabolismus MeSH
- dihydrotestosteron krev metabolismus MeSH
- financování organizované MeSH
- hyperplazie prostaty metabolismus MeSH
- kardiovaskulární nemoci metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- obezita metabolismus MeSH
- složení těla MeSH
- testosteron fyziologie metabolismus MeSH
- tuková tkáň metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
